Dihydrodipyrazolopyridinylbenzamide and -sulfonamide inhibitors of B7-1

ABSTRACT

The present invention provides a compound of formula I and the use thereof for the immunotherapeutic treatment of transplant rejection or autoimmune disease.

BACKGROUND OF THE INVENTION

[0001] This application claims priority from copending provisionalapplication Serial No. 60/399,146, filed Jul. 29, 2002, the entiredisclosure of which is hereby incorporated by reference.

[0002] Regulation of T cell responses plays a primary role indetermining the outcome of auto-immune disease, the development of tumorimmunity, and graft survival following transplantation (Bluestone,et.al. Annu, Rev. Immunol. 1996, 14, 233-258.; Kuchroo, et. al. Crit.Rev. Immunol. 1998, 18, 389-418.; Guinan, et. al. N. Engl. J. Med. 1999,340, 1704-1714.; Abrams et. al. J. Exp. Med. 2000, 192, 681694). Theseimmune responses are controlled by the interaction of molecules on Tcell and antigen presenting cell surfaces. Activation of T cellsrequires two signals, an antigen-specific signal delivered through Tcell antigen receptor, and a second co-stimulatory signal. Thisco-stimulatory signal dictates the outcome for T cells through thebinding of B7-1 and B7-2 expressed on antigen presenting cells to CD28and CTLA-4 on T cells. CD28 engagement by B7-1 or B7-2 amplifies T cellreceptor signaling and stimulates production of cytokines required forT-cell proliferation. On the other hand, CTLA-4 engagement by B7-1 orB7-2 down regulates the immune response (Allison, et. al. Nature 1992,356, 607-609.; Bluestone, et. al. Immunity 1994, 1, 405-413.; Thompson,et. al. Science 1995, 270, 985-988). In experimental disease models,altering these co-stimulatory signals has profound effects on immunity.Blocking B7/CD28 interactions with monoclonal antibodies or solublereceptors results in immunosuppression and enhanced allograft survival,while B7/CTLA-4 blockade results in enhanced anti-tumor immune responses(Larsen, et. al. Nature 1996, 381, 434-438). Consequently, agents, suchas small molecules, which act as inhibitors of cell-cell interactionsmay be useful in the development of effective immunomodulatorymedicines.

[0003] Therefore, it is an object of this invention to provide compoundswhich are useful as immunotherapeutic agents in the treatment oftransplant rejection, autoimmune disease or graft vs host disease.

[0004] It is another object of this invention to provide therapeuticmethods and pharmaceutical compositions useful for the treatment oftransplant rejection, autoimmune disease or graft vs host disease.

[0005] It is a feature of this invention that the compounds provided maybe used to further study and elucidate the interactions of B7-1 with theCD28 receptor.

[0006] These and other objects and features of the invention will becomemore apparent by the detailed description set forth hereinbelow.

SUMMARY OF THE INVENTION

[0007] The present invention provides a compound of formula I

[0008] wherein

[0009] X is CO or SO₂;

[0010] R₁ and R₂ are each independently H, C₁-C₁₀alkyl optionallysubstituted with one or more halogen, hydroxy, C₁-C₄alkoxy, CO₂R₈,CONR₉R₁₀, C₃-C₇cycloalkyl or optionally substituted phenyl groups, or

[0011] phenyl optionally substituted with one to three halogen, hydroxy,C₁-C₆haloalkyl, C₁-C₄alkoxy, CO₂R₁₁, NR₁₂R₁₃ or CN groups;

[0012] R₃ is H, F, Cl, Br or l;

[0013] R₄ and R₅ are each independently H, NH₂, CH₂CH₂OCH₂CH₂OCH₂CH₂NH₂or a C₁-C₆alkyl group optionally substituted with one or two CN, OR₁₄,NR₁₅R₁₆, CO₂R₁₇ or C₃-C₇cycloalkyl group,

[0014] phenyl optionally substituted with one or two halogen, CN, OR₁₄,NR₁₅R₁₆, CO₂R₁₇, COR₁₈, an optionally substituted C₁-C₆alkyl or anoptionally substituted C₂-C₆alkenyl group,

[0015] benzyl optionally substituted with one or two halogen, OR₁₄,COR₁₈, or a C₁-C₃alkyl group optionally substituted with one OR₁₄ group,or

[0016] pyridinyl optionally substituted with one or two halogen, OR₁₄,NR₁₅ R₁₆ or CO₂R₁₇ groups, or

[0017] R₄ and R₅ may be taken together with the atom to which they areattached to form an optionally substituted 5- to 7-membered ringoptionally containing one double bond, a benzofused ring or anadditional heteroatom selected from O, NR₁₉ or S;

[0018] R₆ is phenyl optionally substituted with one to three halogen,NO₂, CN, hydroxy, C₁-C₆alkyl, C₁-C₆alkylthio, C₁-C₆haloalkyl,C₁-C₆alkoxy, phenyl, phenoxy, benzyl, benzyloxy, SO_(n)R₂₀, SO₂NR₂₁R₂₂,CO₂R₂₃ or NR₂₄R₂₅ groups,

[0019] cycloheteroalkyl optionally substituted with one or more halogen,NO₂, CN, hydroxy, C₁-C₆alkyl, C₁-C₆alkylthio, C₁-C₆haloalkyl,C₁-C₆alkoxy, phenyl, phenoxy, benzyl, benzyloxy, SO_(n)R₂₀, SO₂NR₂₁,R₂₂, CO₂R₂₃ or NR₂₄R₂₅ groups, or

[0020] heteroaryl optionally substituted with one or more halogen, NO₂,CN, hydroxy, C₁-C₆alkyl, C₁-C₆alkylthio, C₁-C₆haloalkyl, C₁-C₆alkoxy,phenyl, phenoxy, benzyl, benzyloxy, SO_(n)R₂₀, SO₂NR₂₁R₂₂, CO₂R₂₃ orNR₂₄R₂₅ groups;

[0021] R₈, R₁₁, R₁₇, R₁₈ and R₂₃ are each independently H or aC₁-C₆alkyl, C₃-C₇ cycloalkyl, C₁-C₆haloalkyl, phenyl,C₅-C₇cycloheteroalkyl or heteroaryl group each optionally substituted;

[0022] R₉, R₁₀, R₁₂, R₁₃, R₁₅, R₁₆, R₂₁, R₂₂, R₂₄ and R₂₅ are eachindependently H or a C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆haloalkyl,phenyl, C₅-C₇cycloheteroalkyl or heteroaryl group each optionallysubstituted or each of R₉ and R₁₀ or R₁₂ and R₁₃ or R₁₅ and R₁₆ or R₂,and R₂₂ or R₂₄ and R₂₅ may be taken together with the nitrogen atom towhich they are attached to form a 5- to 7-membered ring optionallycontaining another heteroatom selected from O, N or S;

[0023] n is 0 or an integer of 1 or 2;

[0024] R₁₄ is H, C₁-C₃alkyl or C₁-C₃haloalkyl;

[0025] R₁₉ is H or C₁-C₃alkyl; and

[0026] R₂₀ is a C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆haloalkyl, phenyl,C₅-C₇cyclo-heteroalkyl or heteroaryl group each optionally substituted;or

[0027] the stereoisomers thereof or the pharmaceutically acceptablesalts thereof.

[0028] The present invention also provides methods and compositionsuseful for the immunotherapeutic treatment of transplant rejection,autoimmune disease or graft vs host disease.

DETAILED DESCRIPTION OF THE INVENTION

[0029] Full T cell activation requires both an antigen-specific and asecond co-stimulatory signal. Co-stimulation dictates the outcome for Tcells through the binding of B7-1 and B7-2 expressed onantigen-presenting cells to CD28 and CTLA-4 on T cells (Greenfield, E.A., Nguyen, K. A. and Kuchroo, V. K. (1998) Critical Review ofImmunology, 18, 389-418 and Lenschow, D. J., Walunas, T. L. andBluestone, J. A. (1996) Annual Review of Immunology, 14, 233-258).Animal studies and clinical trials with protein antagonists of theseinteractions indicate considerable promise for immunotherapy intransplantation and autoimmune disease.

[0030] Surprisingly, it has now been found thatdihydrodipyrazolopyridinylbenzamide and-sulfonamide compounds of formulaI are effective inhibitors of B7-1/CD28 binding. Equilibrium dialysisdemonstrates that compounds of formula I bind specifically to human B7-1at a common site. Occupancy of this site by said inhibitors blocked B7-1binding not only to CD28, but also to CTLA-4 (although at much higherconcentrations of inhibitor). Accordingly, the present inventionprovides dihydrodipyrazolopyridinylbenzamide or-sulfonamide B7-1inhibitors of formula I

[0031] wherein

[0032] X is CO or SO₂;

[0033] R₁ and R₂ are each independently H, C₁-C₁₀alkyl optionallysubstituted with one or more halogen, hydroxy, C₁-C₄alkoxy, CO₂R₈,CONR₉R₁₀, C₃-C₇cycloalkyl or optionally substituted phenyl groups, or

[0034] phenyl optionally substituted with one to three halogen, hydroxy,C₁-C₆haloalkyl, C₁-C₄alkoxy, CO₂R₁₁, NR₁₂R₁₃ or CN groups;

[0035] R₃ is H, F, Cl, Br or l;

[0036] R₄ and R₅ are each independently H, NH₂, CH₂CH₂OCH₂CH₂OCH₂CH₂NH₂or a

[0037] C₁-C₆alkyl group optionally substituted with one or two CN, OR₁₄,NR₁₅R₁₆, CO₂R₁₇ or C₃-C₇cycloalkyl group,

[0038] phenyl optionally substituted with one or two halogen, CN, OR₁₄,NR₁₅R₁₆, CO₂R₁₇, COR₁₈, an optionally substituted C₁-C₆alkyl or anoptionally substituted C₂-C₆alkenyl group,

[0039] benzyl optionally substituted with one or two halogen, OR₁₄,COR₁₈, or a C₁-C₃alkyl group optionally substituted with one OR₁₄ group,or

[0040] pyridinyl optionally substituted with one or two halogen, OR₁₄,NR₁₅R₁₆ or CO₂R₁₇ groups, or

[0041] R₄ and R₅ may be taken together with the atom to which they areattached to form an optionally substituted 5- to 7-membered ringoptionally containing one double bond, a benzofused ring or anadditional heteroatom selected from O, NR₁₉ or S;

[0042] R₆ is phenyl optionally substituted with one to three halogen,NO₂, CN, hydroxy, C₁-C₆alkyl, C₁-C₆alkylthio, C₁-C₆haloalkyl,C₁-C₆alkoxy, phenyl, phenoxy, benzyl, benzyloxy, SO_(n)R₂₀, SO₂NR₂₁R₂₂,CO₂R₂₃ or NR₂₄R₂₅ groups,

[0043] cycloheteroalkyl optionally substituted with one or more halogen,NO₂, CN, hydroxy, C₁-C₆alkyl, C₁-C₆alkylthio, C₁-C₆haloalkyl,C₁-C₆alkoxy, phenyl, phenoxy, benzyl, benzyloxy, SO_(n)R₂₀, SO₂NR₂₁,R₂₂,CO₂R₂₃ or NR₂₄R₂₅ groups, or

[0044] heteroaryl optionally substituted with one or more halogen, NO₂,CN, hydroxy, C₁-C₆alkyl, C₁-C₆alkylthio, C₁-C₆haloalkyl, C₁-C₆alkoxy,phenyl, phenoxy, benzyl, benzyloxy, SO_(n)R₂₀, SO₂NR₂₁R₂₂, CO₂R₂₃ orNR₂₄R₂₅ groups;

[0045] R₈, R₁₁, R₁₇, R₁₈ and R₂₃ are each independently H or aC₁-C₆alkyl, C₃-C₇ cycloalkyl, C₁-C₆haloalkyl, phenyl,C₅-C₇cycloheteroalkyl or heteroaryl group each optionally substituted;

[0046] R₉, R₁₀, R₁₂, R₁₃, R₁₅, R₁₆, R₂₁, R₂₂, R₂₄ and R₂₅ are eachindependently H or a C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆haloalkyl,phenyl, C₅-C₇cycloheteroalkyl or heteroaryl group each optionallysubstituted or each of R₉ and R₁₀ or R₁₂ and R₁₃ or R₁₅ and R₁₆ or R₂₁and R₂₂ or R₂₄ and R₂₅ may be taken together with the nitrogen atom towhich they are attached to form a 5- to 7-membered ring optionallycontaining another heteroatom selected from O, N or S;

[0047] n is 0 or an integer of 1 or 2;

[0048] R₁₄ is H, C₁-C₃alkyl or C₁-C₃haloalkyl;

[0049] R₁₉ is H or C₁-C₃alkyl; and

[0050] R₂₀ is a C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆haloalkyl, phenyl,C₅-C₇cyclo-heteroalkyl or heteroaryl group each optionally substituted;or

[0051] the stereoisomers thereof or the pharmaceutically acceptablesalts thereof.

[0052] As used in the specification and claims, the term halogendesignates F, Cl, Br or I and the term cycloheteroalkyl designates aC₅-C₇cycloalkyl ring system containing 1 or 2 heteroatoms, which may bethe same or different, selected from N, O or S and optionally containingone double bond. Exemplary of the cycloheteroalkyl ring systems includedin the term as designated herein are the following rings wherein Z isNR, O or S; and R is H or an optional substituent as describedhereinbelow:

[0053] Similarly, as used in the specification and claims, the termheteroaryl designates a C₅-C₁₀ aromatic ring system containing 1, 2 or 3heteroatoms, which may be the same or different, selected from N, O orS. Such heteroaryl ring systems include pyrrolyl, azolyl, oxazolyl,thiazolyl, imidazolyl, furyl, thienyl, quinolinyl, isoquinolinyl,indolinyl, benzothienyl, benzofuranyl, benzisoxazolyl or the like. Theterm aryl designates a carbocyclic aromatic ring system such as phenyl,naphthyl, anthracenyl or the like. The term haloalkyl as used hereindesignates a C_(n)H_(2n+1), group having from one to 2n+1 halogen atomswhich may be the same or different and the term haloalkoxy as usedherein designates an OC_(n)H_(2n+1), group having from one to 2n+1halogen atoms which may be the same or different.

[0054] In the specification and claims, when the terms C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₇cycloalkyl, cycloheteroalkyl, aryl orheteroaryl are designated as being optionally substituted, thesubstituent groups which are optionally present may be one or more ofthose customarily employed in the development of pharmaceuticalcompounds or the modification of such compounds to influence theirstructure/activity, persistence, absorption, stability or otherbeneficial property. Specific examples of such substituents includehalogen atoms, nitro, cyano, thiocyanato, cyanato, hydroxyl, alkyl,haloalkyl, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, formyl,alkoxycarbonyl, carboxyl, alkanoyl, alkylthio, alkylsulphinyl,alkylsulphonyl, carbamoyl, alkylamido, phenyl, phenoxy, benzyl,benzyloxy, heterocyclyl or cycloalkyl groups, preferably halogen atoms,NO₂, CF₃ or OH groups. Typically, 0-3 substituents may be present,preferably 1 or 2. When any of the foregoing substituents represents orcontains an alkyl substituent group, this may be linear or branched andmay contain up to 12, preferably up to 6, more preferably up to 4 carbonatoms.

[0055] Pharmaceutically acceptable salts may be any acid addition saltformed by a compound of formula I and a pharmaceutically acceptable acidsuch as phosphoric, sulfuric, nitric, hydrochloric, hydrobromic, citric,malic, maleic, malonic, mandelic, succinic, fumaric, tartaric,propionic, acetic, lactic, nitric, sulfonic, p-toluene sulfonic, methanesulfonic acid or the like.

[0056] Compounds of the invention include esters, carbamates or otherconventional prodrug forms, which in general, are functional derivativesof the compounds of the invention and which are readily converted to theinventive active moiety in vivo. Correspondingly, the method of theinvention embraces the treatment of the various conditions describedhereinabove with a compound of formula I or with a compound which is notspecifically disclosed but which, upon administration, converts to acompound of formula I in vivo. Also included are metabolites of thecompounds of the present invention defined as active species producedupon introduction of these compounds into a biological system.

[0057] Compounds of the invention may exist as one or morestereoisomers. The various stereoisomers include enantiomers,diastereomers, atropisomers and geometric isomers. One skilled in theart will appreciate that one stereoisomer may be more active or mayexhibit beneficial effects when enriched relative to the otherstereoisomer(s) or when separated from the other stereoisomer(s).Additionally, the skilled artisan knows how to separate, enrich orselectively prepare said stereoisomers. Accordingly, the presentinvention comprises compounds of Formula I, the stereoisomers thereofand the pharmaceutically acceptable salts thereof. The compounds of theinvention may be present as a mixture of stereoisomers, individualstereoisomers, or as an optically active or enantiomerically pure form.

[0058] Preferred compounds of the invention are those compounds offormula I wherein X is CO. Also preferred are those compounds of formulaI wherein R₁ is H. Another group of preferred compounds of formula I arethose compounds wherein R₆ is a phenyl group optionally substituted withone or two halogen, CN, NO₂, CF₃, C₁-C₃alkoxy or CO₂R₂₃ groups.

[0059] More preferred compounds of the invention are those compounds offormula I wherein X is CO and R₂ is H or C₁-C₃alkyl. Another group ofmore preferred compounds are those compounds of formula I wherein X isCO and R₄ and R₅ are each independently H or a C₁-C₃alkyl, phenyl orbenzyl group each optionally substituted with one or two hydroxy groupsor R₄ and R₅ may be taken together with the atom to which they areattached to form a pyrrolidinyl or morpholinyl group each optionallysubstituted with one carboxy group. Further more preferred compounds offormula I are those compounds wherein X is CO; R₁ is H; R₆ is phenylsubstituted in the 3-position with CF₃; and R₂ is H or CH₃.

[0060] Examples of the preferred compounds of formula I include:

[0061]N-(4-hydroxyphenyl)-3-(6-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,6-dihydrodipyrazolo[3,4-b:3,4-d]pyridin-2(1H)-yl)benzamide;

[0062]N-(2,2-dimethoxyethyl)-N-methyl-3-(6-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,6-dihydrodipyrazolo[3,4-b:3,4-d]pyridin-2(1H)-yl)benzamide;

[0063]6-methyl-2-[3-(1-pyrrolidinylcarbonyl)phenyl]-4-[3-(trifluoromethyl)phenyl]-1,6-dihydrodipyrazolo[3,4-b:3,4-d]pyridin-3(2H)-one;

[0064](2R)-1-[3-(6-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,6-dihydrodipyrazolo[3,4-b:3,4-d]pyridin-2(1H)-yl)benzoyl]-2-pyrrolidinecarboxylic acid;

[0065]N-(3,4-dihydroxybenzyl)-3-(6-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,6-dihydrodipyrazolo[3,4-b:3,4-d]pyridin-2(1H)-yl)benzamide;

[0066]N-(2-hydroxypropyl)-3-(6-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,6-dihydrodipyrazolo[3,4-b:3,4-d]pyridin-2(1H)-yl)benzamide;

[0067]1-{2-chloro-5-[6-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,6-dihydrodipyrazolo[3,4b:3′,4′-d]pyridin-2(1H)-yl]benzoyl}-D-proline;

[0068]2-(4-chloro-3-{[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]carbonyl}phenyl)-6-methyl-4-[3-(trifluoromethyl)phenyl]-1,6-dihydrodipyrazolo[3,4-b:3,4-d]pyridin-3(2H)-one;

[0069]N-(4-hydroxyphenyl-4-{6-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,6-dihydrodipyrazolo[3,4-b:3′,4′-d]pyridin-2(1H)-yl}benzamide;

[0070]N-(2-hydroxyphenyl)-4-{6-methyl-3-oxo-3-[3-(trfluoromethyl)phenyl]-3,6-dihydrodipyrazolo[3,4-b:3′,4′-d]pyridin-2(1H)-yl}benzamide;

[0071]6-methyl-2-[4-(4-morpholinylcarbonyl)phenyl]-4-[3-(trifluoromethyl)phenyl]-1,6-dihydrodipyrazolo[3,4-b:3,4-d]pyridin-3(2H)-one;

[0072]N-[4-(2-hydroxyethyl)phenyl]-4-(6-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,6-dihydrodipyrazolo[3,4-b:3,4-d]pyridin-2(1H)-yl)benzamide;

[0073]N-[3-(1-hydroxyethyl)phenyl]-4-(6-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,6-dihydrodipyrazolo[3,4-b:3,4-d]pyridin-2(1H)-yl)benzamide;

[0074]N-[3-(hydroxymethyl)phenyl]-4-(6-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,6-dihydrodipyrazolo[3,4-b:3,4-d]pyridin-2(1H)-yl)benzamide;

[0075]N-(5-hydroxypentyl)-4-(6-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,6-dihydrodipyrazolo[3,4-b:3,4-d]pyridin-2(1H)-yl)benzenesulfonamide;

[0076]N-benzyl-4-[6-methyl-3-oxo-4-(3-trifluoromethyl-phenyl)-3,6-dihydro-1H-1,2,5,6,7-pentaaza-as-indacen-2-yl]-benzenesulfonamide;

[0077]N-(2-hydroxyethyl)-4-(6-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,6-dihydrodipyrazolo[3,4-b:3,4-d]pyridin-2(1H)-yl)benzenesulfonamide;

[0078] methyl({[4-(6-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,6-dihydrodipyrazolo[3,4-b:3,4-d]pyridin-2(1H)-yl)phenyl]sulfonyl}amino)acetate;

[0079]N-cyclopropylmethyl-4-[6-methyl-3-oxo-4-(3-trifluoromethyl-phenyl)-3,6-dihydro-1H-1,2,5,6,7-pentaaza-as-indacen-2-yl]-benzenesulfonamide;

[0080]({[4-(6-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,6-dihydrodipyrazolo[3,4-b:3,4-d]pyridin-2(1H)-yl)phenyl]sulfonyl}amino)acetic acid;

[0081] the stereoisomers thereof; or the pharmaceutically acceptablesalts thereof.

[0082] Advantageously, the present invention provides a process for thepreparation of a compound of formula I wherein X is CO (Ia) whichcomprises reacting a compound of formula II with an amine, HNR₄R₅, inthe presence of an activating agent such as dicyclohexylcarbodiimide(DCC) and a solvent. The reaction is shown in flow diagram I.

[0083] Activating agents suitable for use in the process of theinvention include dicyclohexylcarbodimide,ethyldimethylaminocarbodimide, hydroxybenzotriaze or the like.

[0084] Solvents suitable for use in the process of the invention includepolar solvents such as tetrahydrofuran, dimethyl formamide,dimethylsulfoxide or the like.

[0085] Compounds of formula I wherein X is SO₂ (lb) may be prepared byprotecting the sulfonamide of formula III to give the bis-protectedcompound of formula IV; alkylating the formula IV compound with thedesired haloalkyl, R₄—X′, in the presence of a base; and deprotectingthe resultant alkylated formula IV compound optionally alkylating asecond time with a haloalkyl, R₅—X′, to give the desired sulfonamide offormula Ib. The reaction is shown in flow diagram II wherein Prepresents a protecting group such as t-butoxy carbonyl and X′represents Cl, Br or l.

[0086] Protecting groups useful in the reactions described hereinaboveinclude t-butyldicarboxylate, benzyl, acetyl, benzyloxycarbonyl, or anyconventional group known to protect a basic nitrogen in standardsynthetic procedures, preferably t-butyidicarboxylate.

[0087] Reaction conditions suitable for deprotection may vary accordingto the nature of the protecting group. For example, if the protectinggroup is t-buty-carbonyl, deprotection takes place in the presence of anacid such as trifluoroacetic acid or HCL optionally in the presence ofan aprotic solvent such as dioxane. If the protecting group is benzyl,deprotection takes place via hydrogenation in the presence of acatalyst, typically 10% Pd/carbon.

[0088] Compounds of formula II or III may be prepared using conventionalsynthetic methods and, if required, standard separation or isolationtechniques.

[0089] For example, for compounds of formula V wherein W represents CO₂Hor SO₂NH₂; an aryl, heteroaryl or heterocycloalkyl ester of formula VImay undergo a Knoevenagel condensation to give the oxo ester for formulaVII; said oxo ester is allowed to react with an aminopyrazole of formulaVIII in the presence of a base to give the hydroxypyrazolopyridine offormula IX; said hydroxypyrazolopyridine is then converted to thecorresponding chloro compound of formula X via reaction with achlorinating agent such as thionyl chloride or phosphorous oxychloride;the resultant chloro compound may undergo an addition-eliminationreaction with a hydrazine of formula XI to give the hydrazinylintermediate of formula XII; and cyclization of the formula XII compoundgives the desired intermediate of formula V. The reaction is illustratedin flow diagram III.

[0090] Cyclization of the intermediate of formula XII is accomplished inthe presence of an acid, such as acetic acid, or a base, such as sodiummethoxide or sodium hydride.

[0091] Advantageously, the compounds of formula I are useful for thetreatment of immune disorders related to or affected by the immuneregulatory protein B7-1 such as transplant rejection, graft vs hostdisease or an autoimmune disease such as multiple sclerosis, rheumatoidarthritis, diabetes mellitus, Grave's disease, pernicious anemia,myasthemia gravis, rheumatic fever, systemic lupus erythematosus,vitiligo, autoimmune Addison's disease, Hashimoto's thyroiditis, Crohn'sdisease or the like. Accordingly, the present invention provides amethod for the treatment of an immune disorder related to or affected bythe immune regulatory protein B7-1 which comprises providing a patientin need thereof with an immunotherapeutically effective amount of acompound of formula I as described hereinabove. The compounds may beprovided by oral or parenteral administration or in any common mannerknown to be an effective administration of an immunotherapeutic agent toa patient in need thereof.

[0092] The term “providing” as used herein with respect to providing acompound or substance embraced by the invention, designates eitherdirectly administering such a compound or substance, or administering aprodrug, derivative or analogue which forms an equivalent amount of thecompound or substance within the body.

[0093] The immunotherapeutically effective amount provided in thetreatment of a specific immune disorder may vary according to thespecific condition(s) being treated, the size, age and response patternof the patient, the severity of the disorder, the judgment of theattending physician and the like. In general, effective amounts fordaily oral administration may be about 0.01 to 1,000 mg/kg, preferablyabout 0.5 to 500 mg/kg and effective amounts for parenteraladministration may be about 0.1 to 100 mg/kg, preferably about 0.5 to 50mg/kg.

[0094] In actual practice, the compounds of the invention are providedby administering the compound or a precursor thereof in a solid orliquid form, either neat or in combination with one or more conventionalpharmaceutical carriers or excipients. Accordingly, the presentinvention provides a pharmaceutical composition which comprises apharmaceutically acceptable carrier and an effective amount of acompound of formula i as described hereinabove.

[0095] Solid carriers suitable for use in the composition of theinvention include one or more substances which may also act as flavoringagents, lubricants, solubilizers, suspending agents, fillers, glidants,compression aides, binders, tablet-disintegrating agents orencapsulating materials. In powders, the carrier may be a finely dividedsolid which is in admixture with a finely divided compound of formula i.In tablets, the formula i compound may be mixed with a carrier havingthe necessary compression properties in suitable proportions andcompacted in the shape and size desired. Said powders and tablets maycontain up to 99% by weight of the formula i compound. Solid carrierssuitable for use in the composition of the invention include calciumphosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch,gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose,polyvinylpyrrolidine, low melting waxes and ion exchange resins.

[0096] Any pharmaceutically acceptable liquid carrier suitable forpreparing solutions, suspensions, emulsions, syrups and elixirs may beemployed in the composition of the invention. Compounds of formula I maybe dissolved or suspended in a pharmaceutically acceptable liquidcarrier such as water, an organic solvent, or a pharmaceuticallyacceptable oil or fat, or a mixture thereof. Said liquid composition maycontain other suitable pharmaceutical additives such as solubilizers,emulsifiers, buffers, preservatives, sweeteners, flavoring agents,suspending agents, thickening agents, coloring agents, viscosityregulators, stabilizers, osmo-regulators, or the like. Examples ofliquid carriers suitable for oral and parenteral administration includewater (particularly containing additives as above, e.g., cellulosederivatives, preferably sodium carboxymethyl cellulose solution),alcohols (including monohydric alcohols and polyhydric alcohols, e.g.,glycols) or their derivatives, or oils (e.g., fractionated coconut oiland arachis oil). For parenteral administration the carrier may also bean oily ester such as ethyl oleate or isopropyl myristate.

[0097] Compositions of the invention which are sterile solutions orsuspensions are suitable for intramuscular, intraperitoneal orsubcutaneous injection. Sterile solutions may also be administeredintravenously. Inventive compositions suitable for oral administrationmay be in either liquid or solid composition form.

[0098] For a more clear understanding, and in order to illustrate theinvention more clearly, specific examples thereof are set forthhereinbelow. The following examples are merely illustrative and are notto be understood as limiting the scope and underlying principles of theinvention in any way.

[0099] The term HNMR designates proton nuclear magnetic resonance. Theterms EtOAc, THF and DMF designate ethyl acetate, tetrahydrofuran anddimethyl formamide, respectively. All chromatography is performed usingSiO₂ as support.

EXAMPLE 1

[0100] Preparation of Ethyl3-Methoxy-3-[(trifluoromethyl)phenyl]-2-propenoate

[0101] A solution of methyl 3-trifluoromethylbenzoate (62.0 g, 0.3 mol)in EtOAc is treated with NaH (60% in mineral oil, 8.4 g), and gentlyheated at 40° C. until a mild exotherm occurs. After the cessation ofreflux, additional NaH is added (12.7 g, total of 0.6 mol) and theresultant mixture is heated at reflux temperature for 16 h, cooled toroom temperature and diluted with methylene chloride and water. Theorganic phase is separated, washed with brine, dried over Na₂SO₄ andconcentrated in vacuo to give an oil residue. The oil is treated withacetonitrile and methanol followed by a solution of TMSCH₂N₂ in hexanes(300 mL, 2M, 0.6 mol), stirred for 36 h and treated with aqueous 5% HCl.After nitrogen evolution ceases, the organic layer is separated, washedwith brine, dried over Na₂SO₄ and concentrated in vacuo. The resultantresidue is chromatographed through a plug of silica gel (4:1, hexanes:EtOAc) to give the title compound as a white solid, 65.5 g, (78% yield).This product is used as is in Example 2.

EXAMPLE 2

[0102] Preparation of Ethyl4-Chloro-1-methyl-6-[3-(trifluoromethyl)phenyl]-1 H-Pyrazolo[3,4-b]pyridine-5-carboxylate

[0103] A solution of ethyl 5-amino-1-methyl-4-pyrazole carboxylate (42.2g, 0.25 mol) in THF is treated with NaH (60% in mineral oil, 25.2 g,0.75 mol), stirred for 30 min, treated with ethyl3-methoxy-3-[(trifluoromethyl)phenyl]-2-propenoate (65.5 g, 0.25 mol),heated at reflux temperature for 36 h, cooled to 0° C., acidified to pH5 with aqueous HCl and extracted with EtOAc. The extracts are combined,washed with brine, dried over Na₂SO₄ and concentrated in vacuo. Theresultant off-white solid residue is triturated with hexanes to give awhite solid. The solid is dissolved in phosphorus oxychloride (750 mL)and heated to reflux temperature for 2 h, cooled to room temperature andconcentrated. This concentrate is dissolved in EtOAc, cooled to 0° C.,and neutralized with aqueous Na₂CO₃. The organic phase is separated,washed with brine, dried over Na₂SO₄ and concentrated. This resultantresidue is chromatographed on silica gel (3:1 hexanes:EtOAc) to affordthe title compound as a white solid 65% (68% yield), characterized byHNMR and mass spectral analyses.

EXAMPLE 3

[0104] Preparation of3-{6-Methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3.6-dihydrodipyrazolo[3,4-b:3.4-d]pyridin-2(1H)-yl}benzoicAcid

[0105] A solution of 3-hydrazinobenzoic acid (7.14 g, 0.047 mol) inethylene glycol is treated with NaO-t-bu (4.5 g, 0.047 mol), stirred at75° C. for 1 h, cooled to room temperature, treated with ethyl4-chloro-1-methyl-6-[3-(trifluoromethyl)phenyl]-1 H-pyrazolo[3,4-b]pyridine-5-carboxylate (6.0 g, 15.6 mmol), heated at 1 00° C. for16 h, treated with additional NaO-t-bu (2.5 g, 0.026 mol), cooled toroom temperature, diluted with water and EtOAc and acidified to pH 3with 3N HCl. The phases are separated. The organic phase is dried overNa₂SO₄ and concentrated in vacuo. The resultant residue is trituratedwith 1.5:1 EtOAc:CH₃OH at 65° C. for 1 h, stirred at room temperaturefor 3 h and filtered. The filtercake is washed with cold EtOAc andair-dried to afford the title product as a tan powder, 5.8 g (82%yield), mp 289-291° C., identified by HNMR and mass spectral analyses.

EXAMPLE 4

[0106] Preparation of 2-Chloro-5-hydrazinobenzoic Acid Hydrochloride

[0107] A solution of 5-amino-2-chlorobenzoic acid (10.3 g, 60 mmol) inconcentrated HCl at 0° C. is treated with an aqueous solution of NaNO₂(4.8 g, 70 mmol) at a rate to maintain a reaction temperature of <10°C., stirred for 0.5 h at 0° to 10° C., treated with a solution of tinchloride dihydrate (33.9 g, 150 mmol) in aqueous HCl at a rate tomaintain a reaction temperature of <10° C., aqueous HCl is addedperiodically, as needed to facilitate stirring, stirred at 5° C. for anadditional 1 h and filtered. The filtercake is recrystallized from waterto afford the title product as white crystals, 9.6 g (71% yield),identified by HNMR analysis.

EXAMPLE 5

[0108] Preparation of2-Chloro-5-{6-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,6-dihydrodipyrazolo[3,4-b:3,4-d]pyridin-2(1H)-yl}Benzoic Acid

[0109] A solution of 2-chloro-5-hydrazinobenzoic acid hydrochloride(2.32 g, 10.4 mmol) in ethylene glycol is treated portionwise withNaO-t-bu (2.0 g, 20.8 mmol) at a rate to maintain a reaction temperatureof <35° C. When addition is complete, the resultant solution is added toa solution of ethyl4-chloro-1-methyl-6-[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine-5-carboxylate(2.0 g, 5.2 mmol) in ethylene glycol at 120° C., stirred at 125° C. for15 h, cooled to room temperature, treated with additional NaO-t-bu (0.76mg, 7.9 mmol), heated at 120° C. for 2-3 h, cooled to room temperature,quenched with dilute HCl (0.6N) and extracted with EtOAc. The extractsare combined, dried over Na₂SO₄ and concentrated in vacuo. The resultantresidue is triturated in 1.25:1 EtOAc:CH₃OH for 1 h at refluxtemperature, cooled to room temperature and filtered. The filtercake iswashed with 4:1 EtOAc:CH₃OH and dried in vacuo to give the title productas a tan solid, 1.2 g (42% yield), mp 335.6-338° C., identified by HNMRand mass spectral analyses.

EXAMPLE 6

[0110] Preparation of6-Methyl-2-[3-(4-morpholinylcarbonyl)phenyl]-1.6-dihydrodipyrazolo-[3,4-b:3.4-d]pyridin-3(2H)-one

[0111] A solution of3-{6-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,6-dihydrodipyrazolo[3,4-b:3,4-d]pyridin-2(1H)-yl}benzoicacid (0.13 g, 0.29 mmol) in DMF is treated with 3 equivalents ofmorpholine, 3 equivalents of ethyldimethylaminocarbodiimide (EDC) HCLsalt and 1.81 equivalents of diisopropyl ethyl amine, stirred at roomtemperature for 16 h, diluted with EtOAc and dilute (0.5N) HCl. Thephases are separated and the organic phase is dried over Na₂SO₄ andconcentrated in vacuo. The resultant residue is purified by flashchromatography (silica gel, 80:20, EtOAc:C₂H₅OH) to afford the titleproduct as a yellow solid, 0.113 g (66% yield), mp 234.8° C. (dec),identified by HNMR and mass spectral analyses.

EXAMPLES 7-100

[0112] Preparation of Dihydrodipyrazolopyridinvibenzamide Compounds

[0113] Using essentially the same procedures described hereinabove andemploying the desired benzoic acid substrate and appropriate amine, thecompounds shown in Table I are obtained and identified by HNMR and massspectral analyses. In Table I, the column headed CON designates the ringposition of the amide function. TABLE I

Ex. No. R3 CON R4 R5 mp ° C. % Yield  7 H 3 H 4-hydroxyphenyl — 26  8 H3 CH₃ CH₂CH(OCH₃)₂ — 70  9 H 3 CH₂—S—CH₂CH₂ 285-289 46 10 H 3CH₂CH₂—S—CH₂CH₂ — 70 11 H 3 CH₂CH₂CH₂CH₂ 255-258 36 12 H 3 Hcyclopropylmethyl — 44 13 H 3 CH₂CH₂CH₂CH(CO₂H)-(2R) 199-202 99 14 H 3CH₃ CH₂CH₂—OH — 19 15 H 3 indole-3-carboxylic acid methyl ester — 54 16H 3 H 4-aminobenzyl 183(dec) 12 17 H 3 H 4-hydroxy-3- 172-176 45methoxybenzyl 18 H 3 H 3,4-dihydroxy-benzyl 177.7-179.8 24 19 H 3 HCH₂CH(OH)CH₃ — 9.5 20 H 3 H CH₂CH₂—OCH₃ — 9.5 21 4-Cl 3 H3,4-dihydroxy-benzyl 212-215 8.0 22 4-Cl 3 CH₂CH₂CH₂CH(CO₂H)-(D) 214-21892 23 4-Cl 3 CH₂CH₂CH₂CH(CH₂OH)-(2R) — 28 24 3-F 4 H 3-(1-hydroxy- >35052 ethyl)phenyl 25 H 4 H 3-(1-hydroxy- 251-254 68.3 ethyl)phenyl 26 H 4CH₂CH₂CH(CO₂CH₃)CH₂CH₂ 187(dec) 45 27 H 4 CH₂CH₂N(CH₃)CH₂CH₂ 191-194 4528 H 4 H CH₂CH₂CH₂—OH 193-195 42 29 H 4 H 3-(methoxy- 210(dec) 85methyl)phenyl 30 3-F 4 CH₂CH₂OCH₂CH₂ 176-179 78 31 3-F 4 H4-(2-hydroxyethyl)- 185(dec) 65 phenyl 32 H 4 H benzyl 189-192 83 33 H 4CH₂CH₂OCH₂CH₂ 287-290 65 34 H 4 H 4-(2-hydroxy- 186-189 72 ethyl)phenyl35 H 4 H 3-(hydroxy- 440(dec) 85 methyl)phenyl 36 H 4CH₂CH₂CH₂CH(CH₂OH)CH₂ 189.8-192.7 63 37 H 4 H 4-hydroxybutyl 280(dec) 4038 H 4 H 3-acetylphenyl 300(dec) 15 39 H 4 H 5-aminopentyl 234.5-236 2040 3-Cl 4 CH₂CH₂OCH₂CH₂ 301-303.5 45 41 3-Cl 4 H 3-(1-hydroxy- 326(dec)50 ethyl)phenyl 42 H 4 H 3-benzoic acid 220-222 27 methyl ester 43 H 4 H5-hydroxy-5,6,- 298(dec) 82 7,8-tetrahydro- 1-naphthalenyl 44 H 3 H NH₂— 95 45 H 3 H CH₂CO₂CH₃ — 67 46 H 3 H CH₂CH₂OCH₂CH₂O— — 23 CH₂CH₂NH₂ 47H 3 H 3,4-difluorophenyl — — 48 H 3 H 3-benzoic acid ethyl — — ester 49H 3 H benzyl — — 50 H 3 H 3-(hydroxymethyl)- — — phenyl 51 H 3 H3-(1-hydroxyethyl)- — — phenyl 52 H 3 3,4-dihydro-2(1H)-isoquinoline —53 H 3 CH₂CH₂CH₂CH(CO₂CH₃)-(2R) — — 54 H 3 CH₂CH₂CH(CO₂H)CH₂CH₂ — — 55 H3 H 4-(2-hydroxy- — — ethyl)phenyl 56 H 3 CH₃ benzyl — — 57 H 3CH₂CH₂CH₂CH(CH₃)CH₂ — — 58 H 3 CH₂CH₂CH₂CH[CON(C₂H₅)₂]CH₂ — — 59 H 3CH₂CH₂CH(OH)CH₂CH₂ — — 60 H 3 H 4-methoxybenzyl — — 61 H 3 CH₃ CH₂CH₂CN— — 62 4-F 3 H 4(2-hydroxy-ethyl) — 53 phenyl 63 H 3 H 3-methoxypropyl —— 64 4-Cl 3 CH₂CH₂CH₂CH(CO₂CH₃)-(D) — — 65 4-F 3 H 3-(1-hydroxy- — 75ethyl)phenyl 66 4-F 3 CH—2CH—2OCH₂CH₂ — 48 67 4-F 3 H 4-hydroxyphenyl —65 68 4-F 3 H 4-(hydroxy- — 78 methyl)phenyl 69 H 3CH₂CH₂CH₂CH(CO₂H)-(L) 168-171 50 70 H 4 H H — 70 71 H 4 H3-hydroxyphenyl — 66 72 H 4 CH₃ CH₂CH₂CN — 81 73 H 4 H 4-hydroxyphenyl —45 74 H 4 H 2-hydroxyphenyl — 52 75 H 4 H cyclopropymethyl — 87 76 H 4 H2-hydroxypropyl — 22 77 H 4 CH₂CH₂SCH₂CH₂ — 85 78 H 4 H4-isopropyiphenyl — 78 79 H 4 H 3-pyridyl — 35 80 H 4 CH₃2,2-dimethoxy-ethyl — 22 81 H 4 CH₂CH₂CH₂CH₂ — 78 82 H 4 H3,4-difluorophenyl — 77 83 H 4 CH₂CH₂SCH₂ — 42 84 H 4 H3-(hydroxymethyl-2- — 58 methylphenyl 85 H 4 CH₃ 3-amino-3-oxo- — —propyl 86 H 4 H 2-(hydroxy- — 53 methyl)phenyl 87 H 4 H4-(hydroxymethyl)- — 75 phenyl 88 H 4 CH₂CH₂CH₂CH[CON(C₂H₅)₂]CH₂ — 61 89H 4 H 3-methoxypropyl 160 (dec) 85 90 H 4 H 3-(dimethyl- — 30amino)propyl 91 H 4 H 4-fluorobenzyl — 68 92 H 4 H 3-aminobenzoic acid —41 methyl ester 93 H 4 CH₃ 2-hydroxyethyl — 33 94 H 4 CH₂CH₂CH(OH)CH₂CH₂— 49 95 H 4 CH₂CH₂CH₂CH(OH)CH₂ 59 96 H 4 H 5-hydroxypentyl — 45 97 H 4 H2-fluorobenzoic acid — 73 methyl ester 98 H 4 H 3,4-dihydroxy-phenyl206-209 64 99 3-F 4 H 4-hydroxyphenyl — 44 100  H 4 H 3-(1-hydroxy- — 65propyl)phenyl

EXAMPLE 101

[0114] Preparation of4-{6-Methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,6-dihydrodipyrazolo[3,4-b:3′,4′-d]pyridin-2-(1H)-yl}Benzenesulfonamide

[0115] A solution of 4-aminosulfonylphenyl hydrazine dihydrochloride(0.87 g, 3.92 mmol) in ethanol is treated with NaO-t-Bu (0.37 g, 3.92mmol), stirred at 70° C. for 20 min, treated with ethyl4-chloro-1-methyl-6-[3-(trifluoromethyl)phenyl]-1 H-pyrazolo[3,4-b]pyridine-5-carboxylate(0.5 g, 1.3 mmol) in ethanol, heated atreflux temperature for 6 days, cooled to room temperature, quenched withwater, acidified to pH 3 with 3NH and extracted with EtOAc. The extractsare combined, dried over Na₂SO₄ and concentrated in vacuo. The resultantresidue is purified by flash chromatography (silica gel, 1:1hexanes:EtOAc to afford the title compound as a white solid, 0.45 g (57%yield), mp 272-274° C., identified by HNMR and mass spectral analyses.

EXAMPLE 102

[0116] Preparation ofN-(5-Hydroxypentyl)-4-{6-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,6-dihydrodipyrazolo[3.4-b:3′,4′-d]pyridin-2(1H)-yl}benzenesulfonamide

[0117] A solution of4-{6-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,6-dihydrodipyrazol[3,4-b:3′,4′-d]pyridin-2-(1H)-yl}benzenesulfonamide(2.78 mmol) in CH₂Cl₂ at 0° C. is treated with triethylamine (21.4 mmol)and di-t-butyl dicarbonate [(Boc)₂O] (3.87 mmol) indimethylaminopyridine, allowed to warm to room temperature, diluted withwater and extracted with CH₂Cl₂. The extracts are combined, dried overNa₂SO₄ and concentrated in vacuo. The resultant residue is flashchromatographed to afford the bis(t-butoxycarbonyl) intermediate in 51%yield. A solution of this intermediate (0.145 mmol) in THF is treatedwith pentane-1,5-diol (0.29 mmol), triphenyl phosphine (0.29 mmol) anddiisopropylazodicarboxylate (0.261 mmol), stirred at room temperaturefor 1 6 h, poured into cold NaHCO₃ and extracted with EtOAc. Theextracts are combined, dried over Na₂SO₄ and concentrated in vacuo togive a residue. This residue is chromatographed to afford the mono-Bocprecursor to the title compound in 43% yield. This precursor (0.037mmol) is treated with cold trifluoroacetic acid (0.2 mL), stirred at 0°C. for 40 min, diluted with water, treated with saturated NaHCO₃ to pH 8and extracted with EtOAc. The extracts are combined, dried over MgSO₄and concentrated in vacuo. The resultant residue is flashchromatographed (silica gel, 100% EtOAc to 10% methanol in EtOAcgradient elution) to afford the title product as a white solid, 0.017mmol (45% yield), identified by HNMR and mass spectral analyses.

EXAMPLES 103-107

[0118] Preparation of DihydrodipyrazolopyridinylbenzenesulfonamideCompounds

[0119] Using essentially the same procedure described in Example 102hereinabove and employing the appropriate reagent, the compounds shownin Table II are obtained and identified by HNMR and mass spectralanalyses. TABLE II

Ex No. R4 R5 % Yield 103 H benzyl 83 104 H 2-hydroxyethyl 68 105 HCH₂CO₂CH₃ 37 106 H cyclopropylmethyl 16 107 H CH₂CO₂H 67

EXAMPLE 108

[0120] Evaluation of B7-1/CD28 Binding Inhibition for Test Compounds

[0121] CD28/B7-1 ELISA

[0122] Wells are coated with 300 ng CD28-Fc in carbonate buffer (pH 9.4)overnight at 4° C., blocked with 1% bovine serum albumin intris-buffered saline (TBS) for 1 h at 22° C. and washed 3 times in TBSprior to assay. The detection complex is formed as follows:B7-1-Fc-biotin, prepared using NHS-LC-biotin (Pierce #21335) accordingto the manufacturers instructions (4.1 moles biotin/mole Fc), is addedat 0.8 ug/ml to streptavidin-alkaline phosphatase (Caltag Sal008) at1:1000 in TBS. A solution of test compound in dimethylsulfoxide (1%final) are added to this complex and incubated 30 min at 22° C.Detection complex (+/−inhibitors) is then added to the CD28 coated wellsfor 25 min at 22° C., washed 5 times with TBS, developed with thecolorimetric substrate pNPP (Pierce #34045) in diethanolamine/MgCl₂buffer (pH 9.5) and read at 405 nm. The inhibition constant (IC₅₀) iscalculated by subtracting background binding and comparing touninhibited (DMSO alone) controls. The inhibition constant representsthe concentration of test compound required to achieve 50% inhibition.The results are shown in Table III. TABLE III Example B7-1/CD28Inhibition Number IC50 (nM) 6 54 7 38 8 31 9 53 10 70 11 44 12 80 13 2014 61 15 63 16 57 17 55 18 9 19 45 20 62 21 22 22 44 23 43 24 110 25 326 90 27 500 28 98 29 110 30 310 31 64 32 79 33 13 34 23 35 17 36 180 3788 38 44 39 140 40 84 41 550 42 94 43 300 44 80 45 100 46 150 47 280 48440 49 120 50 100 51 130 52 300 53 270 54 860 55 110 56 180 57 92 58 11059 105 60 180 61 330 62 380 63 180 64 180 65 1000 66 2400 67 280 68 37069 100 70 38 71 140 72 110 73 11 74 17 75 107 76 50 77 140 78 120 79 18080 170 81 110 82 120 83 110 84 90 85 1800 86 40 87 44 88 290 89 110 90160 91 67 92 73 93 330 94 1200 95 390 96 92 97 640 98 36 99 31 100 800102 670 103 1500 104 950 105 340 106 900 107 450

What is claimed is:
 1. A compound of formula I

wherein X is CO or SO₂; R₁ and R₂ are each independently H, C₁-C₁₀alkyloptionally substituted with one or more halogen, hydroxy, C₁-C₄alkoxy,CO₂R₈, CONR₉R₁₀, C₃-C₇cycloalkyl or optionally substituted phenylgroups, or phenyl optionally substituted with one to three halogen,hydroxy, C₁-C₆haloalkyl, C₁-C₄alkoxy, CO₂R₁₁, NR₁₂R₁₃ or CN groups; R₃is H, F, Cl, Br or l; R₄ and R₅ are each independently H, NH₂,CH₂CH₂OCH₂CH₂OCH₂CH₂NH₂ or a C₁-C₆alkyl group optionally substitutedwith one or two CN, OR₁₄, NR₁₅ R₁₆, CO₂R₁₇ or C₃-C₇cycloalkyl group,phenyl optionally substituted with one or two halogen, CN, OR₁₄,NR₁₅R₁₆, CO₂ R₁₇, COR₁₈, an optionally substituted C₁-C₆alkyl or anoptionally substituted C₂-C₆alkenyl group, benzyl optionally substitutedwith one or two halogen, OR₁₄, COR₁₈, or a C₁-C₃alkyl group optionallysubstituted with one OR₁₄ group, or pyridinyl optionally substitutedwith one or two halogen, OR₁₄, NR₁₅R₁₆ or CO₂R₁₇ groups, or R₄ and R₅may be taken together with the atom to which they are attached to forman optionally substituted 5- to 7-membered ring optionally containingone double bond, a benzofused ring or an additional heteroatom selectedfrom O, NR₁₉ or S; R₆ is phenyl optionally substituted with one to threehalogen, NO₂, CN, hydroxy, C₁-C₆alkyl, C₁-C₆alkylthio, C₁-C₆haloalkyl,C₁-C₆alkoxy, phenyl, phenoxy, benzyl, benzyloxy, SO_(n)R₂₀, SO₂NR₂₁R₂₂,CO₂R₂₃ or NR₂₄R₂₅ groups, cycloheteroalkyl optionally substituted withone or more halogen, NO₂, CN, hydroxy, C₁-C₆alkyl, C₁-C₆alkylthio,C₁-C₆haloalkyl, C₁-C₆alkoxy, phenyl, phenoxy, benzyl, benzyloxy,SO_(n)R₂₀, SO₂NR₂₁, R₂₂, CO₂R₂₃ or NR₂₄R₂₅ groups, or heteroaryloptionally substituted with one or more halogen, NO₂, CN, hydroxy,C₁-C₆alkyl, C₁-C₆alkylthio, C₁-C₆haloalkyl, C₁-C₆alkoxy, phenyl,phenoxy, benzyl, benzyloxy, SO_(n)R₂₀, SO₂NR₂₁R₂₂, CO₂R₂₃ or NR₂₄R₂₅groups; R₈, R₁₁, R₁₇, R₁₈ and R₂₃ are each independently H or aC₁-C₆alkyl, C₃-C₇ cycloalkyl, C₁-C₆haloalkyl, phenyl,C₅-C₇cycloheteroalkyl or heteroaryl group each optionally substituted;R₉, R₁₀, R₁₂, R₁₃, R₁₅, R₁₆, R₂₁, R₂₂, R₂₄ and R₂₅ are eachindependently H or a C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆haloalkyl,phenyl, C₅-C₇cycloheteroalkyl or heteroaryl group each optionallysubstituted or each of R₉ and R₁₀ or R₁₂ and R₁₃ or R₁₅ and R₁₆ or R₂,and R₂₂ or R₂₄ and R₂₅ may be taken together with the nitrogen atom towhich they are attached to form a 5- to 7-membered ring optionallycontaining another heteroatom selected from O, N or S; n is O or aninteger of 1 or 2; R₁₄ is H, C₁-C₃alkyl or C₁-C₃haloalkyl; R₁₉ is H orC₁-C₃alkyl; and R₂₀ is a C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆haloalkyl,phenyl, C₅-C₇cycloheteroalkyl or heteroaryl group each optionallysubstituted; or the stereoisomers thereof or the pharmaceuticallyacceptable salts thereof.
 2. The compound according to claim 1 wherein Xis CO.
 3. The compound according to claim 1 wherein R₁ is H.
 4. Thecompound according to claim 1 wherein R₁ is H. The compound according toclaim 1 wherein R₆ is a phenyl group optionally substituted with one ortwo CN, NO₂, halogen, CF₃, C₁-C₃alkoxy or CO₂R₂₃ groups.
 5. The compoundaccording to claim 2 wherein R₂ is H or C₁-C₃alkyl.
 6. The compoundaccording to claim 2 wherein R₄ and R₅ are each independently H or aC₁-C₃alkyl, phenyl or benzyl group each optionally substituted with oneor two hydroxy groups or R₄ and R₅ may be taken together with the atomto which they are attached to form a pyrrolidinyl or morpholinyl ringeach optionally substituted with one carboxy group.
 7. The compoundaccording to claim 5 wherein R₆ is phenyl optionally substituted in the3-position with CF₃.
 8. The compound according to claim 7 wherein R₁ isH.
 9. The compound according to claim 7 wherein R₁ is H. The compoundaccording to claim 1 selected from the group consisting of:N-(4-hydroxyphenyl)-3-(6-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,6-dihydrodipyrazolo[3,4-b:3,4-d]pyridin-2(1H)-yl)benzamide;N-(2,2-dimethoxyethyl)-N-methyl-3-(6-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,6-dihydrodipyrazolo[3,4-b:3,4-d]pyridin-2(1H)-yl)benzamide;6-methyl-2-[3-(1-pyrrolidinylcarbonyl)phenyl]-4-[3-(trifluoromethyl)phenyl]-1,6-dihydrodipyrazolo[3,4-b:3,4-d]pyridin-3(2H)-one;(2R)-1-[3-(6-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,6-dihydrodipyrazolo[3,4-b:3,4-d]pyridin-2(1H)-yl)benzoyl]-2-pyrrolidinecarboxylic acid;N-(3,4-dihydroxybenzyl)-3-(6-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,6-dihydrodipyrazolo[3,4-b:3,4-d]pyridin-2(1H)-yl)benzamide;N-(2-hydroxypropyl)-3-(6-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,6-dihydrodipyrazolo[3,4-b:3,4-d]pyridin-2(1H)-yl)benzamide;1-{2-chloro-5-[6-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,6-dihydrodipyrazolo[3,4-b:3′,4′-d]pyridin-2(1H)-yl]benzoyl}-D-proline;2-(4-chloro-3-{[(2R)-2-(hydroxymethyl)pyrrolidin-1-yl]carbonyl}phenyl)-6-methyl-4-[3-(trifluoromethyl)phenyl]-1,6-dihydrodipyrazolo[3,4-b:3,4-d]pyridin-3(2H)-one;N-(4-hydroxyphenyl-4-{6-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,6-dihydrodipyrazolo[3,4-b:3′,4′-d]pyridin-2(1H)-yl}benzamide;N-(2-hydroxyphenyl)-4-{6-methyl-3-oxo-3-[3-(trfluoromethyl)phenyl]-3,6-dihydrodipyrazolo[3,4-b:3′,4′-d]pyridin-2(1H)-yl}benzamide;6-methyl-2-[4-(4-morpholinylcarbonyl)phenyl]-4-[3-(trifluoromethyl)phenyl]-1,6-dihydrodipyrazolo[3,4-b:3,4-d]pyridin-3(2H)-one;N-[4-(2-hydroxyethyl)phenyl]-4-(6-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,6-dihydrodipyrazolo[3,4-b:3,4-d]pyridin-2(1H)-yl)benzamide;N-[3-(1-hydroxyethyl)phenyl]-4-(6-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,6-dihydrodipyrazolo[3,4-b:3,4-d]pyridin-2(1H)-yl)benzamide;N-[3-(hydroxymethyl)phenyl]-4-(6-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,6-dihydrodipyrazolo[3,4-b:3,4-d]pyridin-2(1H)-yl)benzamide;N-(5-hydroxypentyl)-4-(6-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,6-dihydrodipyrazolo[3,4-b:3,4-d]pyridin-2(1H)-yl)benzenesulfonamide;N-benzyl-4-[6-methyl-3-oxo-4-(3-trifluoromethyl-phenyl)-3,6-dihydro-1H-1,2,5,6,7-pentaaza-as-indacen-2-yl]-benzenesulfonamide;N-(2-hydroxyethyl)-4-(6-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,6-dihydrodipyrazolo[3,4-b:3,4-d]pyridin-2(1H)-yl)benzenesulfonamide;methyl({[4-(6-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,6-dihydrodipyrazolo[3,4-b:3,4-d]pyridin-2(1H)-yl)phenyl]sulfonyl}amino)acetate;N-cyclopropylmethyl-4-[6-methyl-3-oxo-4-(3-trifluoromethyl-phenyl)-3,6-dihydro-1H-1,2,5,6,7-pentaaza-as-indacen-2-yl]-benzenesulfonamide;({[4-(6-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,6-dihydrodipyrazolo[3,4-b:3,4-d]pyridin-2(1H)-yl)phenyl]sulfonyl}amino)acetic acid; thestereoisomers thereof; and the pharmaceutically acceptable saltsthereof.
 10. A method for the treatment of an immune disorder related toor affected by the immune regulatory protein B7-1 which comprisesproviding a patient in need thereof an immunotherapeutically effectiveamount of a compound of formula

wherein X is CO or SO₂; R₁ and R₂ are each independently H, C₁-C₁₀alkyloptionally substituted with one or more halogen, hydroxy, C₁-C₄alkoxy,CO₂R₈, CONR₉R₁₀, C₃-C₇cycloalkyl or optionally substituted phenylgroups, or phenyl optionally substituted with one to three halogen,hydroxy, C₁-C₆haloalkyl, C₁-C₄alkoxy, CO₂R₁₁, NR₁₂R₁₃ or CN groups; R₃is H, F, Cl, Br or l; R₄ and R₅ are each independently H, NH₂,CH₂CH₂OCH₂CH₂OCH₂CH₂NH₂ or a C₁-C₆alkyl group optionally substitutedwith one or two CN, OR₁₄, NR₁₅R₁₆, CO₂R₁₇ or C₃-C₇cycloalkyl group,phenyl optionally substituted with one or two halogen, CN, OR₁₄,NR₁₅R₁₆, CO₂R₁₇, COR₁₈, an optionally substituted C₁-C₆alkyl or anoptionally substituted C₂-C₆alkenyl group, benzyl optionally substitutedwith one or two halogen, OR₁₄, COR₁₈, or a C₁-C₃alkyl group optionallysubstituted with one OR₁₄ group, or pyridinyl optionally substitutedwith one or two halogen, OR₁₄, NR₁₅R₁₆ or CO₂R₁₇ groups, or R₄ and R₅may be taken together with the atom to which they are attached to forman optionally substituted 5- to 7-membered ring optionally containingone double bond, a benzofused ring or an additional heteroatom selectedfrom O, NR₁₉ or S; R₆ is phenyl optionally substituted with one to threehalogen, NO₂, CN, hydroxy, C₁-C₆alkyl, C₁-C₆alkylthio, C₁-C₆haloalkyl,C₁-C₆alkoxy, phenyl, phenoxy, benzyl, benzyloxy, SO_(n)R₂₀, SO₂NR₂₁R₂₂,CO₂R₂₃ or NR₂₄R₂₅ groups, cycloheteroalkyl optionally substituted withone or more halogen, NO₂, CN, hydroxy, C₁-C₆alkyl, C₁-C₆alkylthio,C₁-C₆haloalkyl, C₁-C₆alkoxy, phenyl, phenoxy, benzyl, benzyloxy,SO_(n)R₂₀, SO₂NR₂₁,R₂₂, CO₂R₂₃ or NR₂₄R₂₅ groups, or heteroaryloptionally substituted with one or more halogen, NO₂, CN, hydroxy,C₁-C₆alkyl, C₁-C₆alkylthio, C₁-C₆haloalkyl, C₁-C₆alkoxy, phenyl,phenoxy, benzyl, benzyloxy, SO_(n)R20, SO₂NR₂₁R₂₂, CO₂R₂₃ or NR₂₄R₂₅groups; R₈, R₁₁, R₁₇, R₁₈ and R₂₃ are each independently H or aC₁-C₆alkyl, C₃-C₇ cycloalkyl, C₁-C₆haloalkyl, phenyl,C₅-C₇cycloheteroalkyl or heteroaryl group each optionally substituted;R₉, R₁₀, R₁₂, R₁₃, R₁₅, R₁₆, R₂₁, R₂₂, R₂₄ and R₂₅ are eachindependently H or a C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆haloalkyl,phenyl, C₅-C₇cycloheteroalkyl or heteroaryl group each optionallysubstituted or each of R₉ and R₁₀ or R₁₂ and R₁₃ or R₁₅ and R₁₆ or R₂₁and R₂₂ or R₂₄ and R₂₅ may be taken together with the nitrogen atom towhich they are attached to form a 5- to 7-membered ring optionallycontaining another heteroatom selected from O, N or S; n is 0 or aninteger of 1 or 2; R₁₄ is H, C₁-C₃alkyl or C₁-C₃haloalkyl; R₁₉ is H orC₁-C₃alkyl; and R₂₀ is a C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆haloalkyl,phenyl, C₅-C₇cycloheteroalkyl or heteroaryl group each optionallysubstituted; or the stereoisomers thereof or the pharmaceuticallyacceptable salts thereof.
 11. The method according to claim 10 whereinsaid disorder is transplant rejection.
 12. The method according to claim10 wherein said disorder is an autoimmune disease.
 13. The methodaccording to claim 10 wherein said disorder is graft vs. host disease.14. The method according to claim 12 wherein said disease is multiplesclerosis or rheumatoid arthritis.
 15. A pharmaceutical compositionwhich comprises a pharmaceutically acceptable carrier and an effectiveamount of a compound of formula I

wherein X is CO or SO₂; R₁ and R₂ are each independently H, C₁-C₁₀alkyloptionally substituted with one or more halogen, hydroxy, C₁-C₄alkoxy,CO₂R₈, CONR₉R₁₀, C₃-C₇cycloalkyl or optionally substituted phenylgroups, or phenyl optionally substituted with one to three halogen,hydroxy, C₁-C₆haloalkyl, C₁-C₄alkoxy, CO₂R₁₁, NR₁₂R₁₃ or CN groups; R₃is H, F, Cl, Br or l; R₄ and R₅ are each independently H, NH₂,CH₂CH₂OCH₂CH₂OCH₂CH₂NH₂ or a C₁-C₆alkyl group optionally substitutedwith one or two CN, OR₁₄, NR₁₅ μl₆, CO₂ μl₇ or C₃-C₇cycloalkyl group,phenyl optionally substituted with one or two halogen, CN, OR₁₄,NR₁₅R₁₆, CO₂R₁₇, COR₁₈, an optionally substituted C₁-C₆alkyl or anoptionally substituted C₂-C₆alkenyl group, benzyl optionally substitutedwith one or two halogen, OR₁₄, COR₁₈, or a C₁-C₃alkyl group optionallysubstituted with one OR₁₄ group, or pyridinyl optionally substitutedwith one or two halogen, OR₁₄, NR₁₅R₁₆ or CO₂R₁₇ groups, or R₄ and R₅may be taken together with the atom to which they are attached to forman optionally substituted 5- to 7-membered ring optionally containingone double bond, a benzofused ring or an additional heteroatom selectedfrom O, NR₁₉ or S; R₆ is phenyl optionally substituted with one to threehalogen, NO₂, CN, hydroxy, C₁-C₆alkyl, C₁-C₆alkylthio, C₁-C₆haloalkyl,C₁-C₆alkoxy, phenyl, phenoxy, benzyl, benzyloxy, SO_(n)R₂₀, SO₂NR₂₁R₂₂,CO₂R₂₃ or NR₂₄R₂₅ groups, cycloheteroalkyl optionally substituted withone or more halogen, NO₂, CN, hydroxy, C₁-C₆alkyl, C₁-C₆alkylthio,C₁-C₆haloalkyl, C₁-C₆alkoxy, phenyl, phenoxy, benzyl, benzyloxy,SO_(n)R₂₀, SO₂NR₂₁, R₂₂, CO₂R₂₃ or NR₂₄R₂₅ groups, or heteroaryloptionally substituted with one or more halogen, NO₂, CN, hydroxy,C₁-C₆alkyl, C₁-C₆alkylthio, C₁-C₆haloalkyl, C₁-C₆alkoxy, phenyl,phenoxy, benzyl, benzyloxy, SO_(n)R₂₀, SO₂NR₂₁R₂₂, CO₂R₂₃ or NR₂₄R₂₅groups; R₈, R₁₁, R₁₇, R₁₈ and R₂₃ are each independently H or aC₁-C₆alkyl, C₃-C₇ cycloalkyl, C₁-C₆haloalkyl, phenyl,C₅-C₇cycloheteroalkyl or heteroaryl group each optionally substituted;R₉, R₁₀, R₁₂, R₁₃, R₁₅, R₁₆, R₂₁, R₂₂, R₂₄ and R₂₅ are eachindependently H or a C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆haloalkyl,phenyl, C₅-C₇cycloheteroalkyl or heteroaryl group each optionallysubstituted or each of R₉ and R₁₀ or R₁₂ and R₁₃ or R₁₅ and R₁₆ or R₂₁and R₂₂ or R₂₄ and R₂₅ may be taken together with the nitrogen atom towhich they are attached to form a 5- to 7-membered ring optionallycontaining another heteroatom selected from O, N or S; n is 0 or aninteger of 1 or 2; R₁₄ is H, C₁-C₃alkyl or C₁-C₃haloalkyl; R₁₉ is H orC₁-C₃alkyl; and R₂₀ is a C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆haloalkyl,phenyl, C₅-C₇Cyclo-heteroalkyl or heteroaryl group each optionallysubstituted; or the stereoisomers thereof or the pharmaceuticallyacceptable salts thereof.
 16. The composition according to claim 15having a formula I compound wherein X is CO.
 17. The compositionaccording to claim 16 having a formula I compound wherein R₁ is H. 18.The composition according to claim 17 having a formula I compoundwherein R₂ is H or CH₃.
 19. The composition according to claim 18 havinga formula I compound wherein R₆ is phenyl optionally substituted in the3-position with CF₃.
 20. A process for the preparation of a compound offormula Ia

wherein R₁ and R₂ are each independently H, C₁-C₁₀alkyl optionallysubstituted with one or more halogen, hydroxy, C₁-C₄alkoxy, CO₂R₈,CONR₉R₁₀, C₃C₇cycloalkyl or optionally substituted phenyl groups, orphenyl optionally substituted with one to three halogen, hydroxy,C₁-C₆haloalkyl, C₁-C₄alkoxy, CO₂R₁₁, NR₁₂R₁₃ or CN groups; R₃ is H, F,Cl, Br or l; R₄ and R₅ are each independently H, NH₂,CH₂CH₂OCH₂CH₂OCH₂CH₂NH₂ or a C₁-C₆alkyl group optionally substitutedwith one or two CN, OR₁₄, NR₁₅R₁₆, CO₂R₁₇ or C₃-C₇cycloalkyl group,phenyl optionally substituted with one or two halogen, CN, OR₁₄,NR₁₅R₁₆, CO₂R₁₇, COR₁₈, an optionally substituted C₁-C₆alkyl or anoptionally substituted C₂-C₆alkenyl group, benzyl optionally substitutedwith one or two halogen, OR₁₄, COR₁₈, or a C₁-C₃alkyl group optionallysubstituted with one OR₁₄ group, or pyridinyl optionally substitutedwith one or two halogen, OR₁₄, NR₁₅R₁₆ or CO₂R₁₇ groups, or R₄ and R₅may be taken together with the atom to which they are attached to forman optionally substituted 5- to 7-membered ring optionally containingone double bond, a benzofused ring or an additional heteroatom selectedfrom O, NR₁₉ or S; R₆ is phenyl optionally substituted with one to threehalogen, NO₂, CN, hydroxy, C₁-C₆alkyl, C₁-C₆alkylthio, C₁-C₆haloalkyl,C₁-C₆alkoxy, phenyl, phenoxy, benzyl, benzyloxy, SO_(n)R₂₀, SO₂NR₂,R₂₂,CO₂R₂₃ or NR₂₄R₂₅ groups, cycloheteroalkyl optionally substituted withone or more halogen, NO₂, CN, hydroxy, C₁-C₆alkyl, C₁-C₆alkylthio,C₁-C₆haloalkyl, C₁-C₆alkoxy, phenyl, phenoxy, benzyl, benzyloxy,SO_(n)R₂₀, SO₂NR₂₁, R₂₂, CO₂R₂₃ or NR₂₄R₂₅ groups, or heteroaryloptionally substituted with one or more halogen, NO₂, CN, hydroxy,C₁-C₆alkyl, C₁-C₆alkylthio, C₁-C₆haloalkyl, C₁-C₆alkoxy, phenyl,phenoxy, benzyl, benzyloxy, SO_(n)R₂₀, SO₂NR₂₁R₂₂, CO₂R₂₃ or NR₂₄R₂₅groups; R₈, R₁₁, R₁₇, R₁₈ and R₂₃ are each independently H or aC₁-C₆alkyl, C₃-C₇ cycloalkyl, C₁-C₆haloalkyl, phenyl,C₅-C₇cycloheteroalkyl or heteroaryl group each optionally substituted;R₉, R₁₀, R₁₂, R₁₃, R₁₅, R₁₆, R₂₁, R₂₂, R₂₄ and R₂₅ are eachindependently H or a C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆haloalkyl,phenyl, C₅-C₇cycloheteroalkyl or heteroaryl group each optionallysubstituted or each of R₉ and R₁₀ or R₁₂ and R₁₃ or R₁₅ and R₁₆ or R₂,and R₂₂ or R₂₄ and R₂₅ may be taken together with the nitrogen atom towhich they are attached to form a 5- to 7-membered ring optionallycontaining another heteroatom selected from O, N or S; n is 0 or aninteger of 1 or 2; R₁₄ is H, C₁-C₃alkyl or C₁-C₃haloalkyl; R₁₉ is H orC₁-C₃alkyl; and R₂₀ is a C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₆haloalkyl,phenyl, C₅-C₇cyclo-heteroalkyl or heteroaryl group each optionallysubstituted which process comprises reacting a compound of formula II

wherein R₁, R₂, R₃ and R₆ are defined hereinabove with an amine, HNR₄R₅,in the presence of an activating agent and a solvent.